PROJECT SUMMARY/ABSTRACT: This project will investigate the neurobiology of forgetting in a model of memory with known clinical relevance. Through study of long-term sensitization memory in Aplysia californica we have found that forgetting is accompanied by changes in gene expression that could work to actively degrade stored memories (Conte et al., 2017). However, even when forgetting seems complete, there are latent traces of initial learning that persist, including both rapid-relearning (savings) and continued changes in gene expression (Perez et al., 2018). We have integrated our results into a dual-process model that suggests 1) that encoding produces both synaptic and structural changes that foster recall, 2) that an active forgetting processes erodes the synaptic changes, impairing recall, but 3) that a structural memory trace persists through epigenetic mechanisms to support rapid re-learning (Patel et al., 2018). We will test 3 key predictions of this model to provide new insights into the neurobiology of forgetting: ? Is forgetting an active process? Forgetting may not be a passive decay of stored information but may reflect instead intrinsic neuronal mechanisms that actively work to disrupt maintenance mechanisms. If so, it should be possible to experimentally manipulate the forgetting process. We will attempt to speed and slow rates of forgetting by manipulating neuromodulatory signaling from FMRFamide, a peptide transmitter. FMRFamide functions as a memory suppressor and our previous work shows it is strongly and persistently up-regulated as forgetting occurs. ? What is the nature of savings memory? Savings is the rapid acquisition of information which seemed to have been forgotten. Savings suggests that some trace of the original memory remains intact, but the molecular nature of savings remains unclear. We will characterize the transcriptional correlates of savings memory using microarray and qPCR. Our results will indicate if savings represents a lower threshold for learning or a recovery of an existing but latent memory trace. ? Do epigenetic mechanisms contribute to memory persistence? As LTS forgetting occurs, the initial transcriptional changes evoked by learning collapse (Perez et al. 2018a). Remarkably, 7 transcripts remain strongly regulated for weeks after LTS recall has fully decayed, potentially mediating savings memory (Patel et al., 2018). We will follow up promising pilot data by testing if learning alters patterns of DNA methylation. We will be able to test two specific neuron types of known behavioral relevance for changes during memory maintenance and forgetting. The research proposed in this renewal will further advance a generative line of inquiry into the fundamental mechanisms of forgetting while providing exceptional opportunities for undergraduate involvement.